The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds for the preparation of a medicament which particularly acts on the central nervous system.
Many diseases of the central nervous system are influenced by the adrenergic, the dopaminergic, and the serotonergic neurotransmitter systems. For example, serotonin has been implicated in a number of diseases and conditions which originate in the central nervous system. A number of pharmacological and genetic experiments involving receptors for serotonin strongly implicate the 5-HT2c receptor subtype in the regulation of food intake (Obes. Res. 1995, 3, Suppl. 4, 449S-462S). The 5-HT2c receptor subtype is transcribed and expressed in hypothalamic structures associated with appetite regulation. It has been demonstrated that the 5-HT2c receptor agonist m-chlorophenylpiperazine (mCPP), which has some preference for the 5-HT2c receptor, reduces food intake in mice that express the normal 5-HT2c receptor while the compound lacks activity in mice expressing the mutated inactive form of the 5-HT2c receptor (Nature 1995, 374, 542-546). In a recent clinical study, a slight but sustained reduction in body weight was obtained after 2 weeks of treatment with mCPP in obese subjects (Psychopharmacology 1997, 133, 309-312). Recently, a series of pyrrolo[3,2,1-ij]quinoline derivatives was identified to be 5-HT2C receptor agonists having selectivity over the 5-HT2A receptor (Isaac M., et al., Bioorg. Med. Chem. Lett. 2000, 10, 919-921). The compounds are said to offer a novel approach to the treatment of obesity and epilepsy.
Weight reduction has also been reported from clinical studies with other xe2x80x9cserotonergicxe2x80x9d agents (see, e.g., IDrugs 1998, 1, 456-470). For example, the 5-HT reuptake inhibitor fluoxetine and the 5-HT releasing agent/reuptake inhibitor dexfenflurarnine have exhibited weight reduction in controlled studies. However, currently available drugs that increase serotonergic transmission appear to have only a moderate and, in some cases, transient effects on the body weight.
The 5-HT2c receptor subtype has also been suggested to be involved in CNS disorders such as depression and anxiety (Exp. Opin. Invest. Drugs 1998, 7, 1587-1599; IDrugs 1999, 2, 109-120).
The 5-HT2c receptor subtype has further been suggested to be involved in urinary disorders such as urinary incontinence (IDrugs 1999, 2, 109-120).
Compounds which have a selective effect on the 5-HT2c receptor may therefore have a therapeutic potential in the treatment of disorders like those mentioned above. Of course, selectivity also reduces the potential for adverse effects mediated by other serotonin receptors.
U.S. Pat. No. 3,253,989 discloses the use of mCPP as an anorectic agent.
EP-A1-863 136 discloses azetidine and pyrrolidine derivatives which are selective 5-HT2c receptor agonists having antidepressant activity and which can be used for treating or preventing serotonin-related diseases, including eating disorders and anxiety.
EP-A-657 426 discloses tricyclic pyrrole derivatives having activity on the 5-HT2c receptor and which inter alia may be used for treating eating disorders.
EP-A-655 440 discloses l-aminoethylindoles having activity on the 5-HT2c receptor and which may be used for treating eating disorders.
EP-A-572 863 discloses pyrazinoindoles having activity on the 5-HT2c receptor and which may be used for treating eating disorders.
J. Med. Chem. 1978, 21, 536-542 and U.S. Pat. No. 4,081,542 disclose a series of piperazinylpyrazines having central serotonin-mimetic activity.
J. Med. Chem. 1981. 24, 93-101 discloses a series of piperazinylquinoxalines with central serotoninmimetic activity.
WO 00/12475 discloses indoline derivatives as 5-HT2b and/or 5-HT2C receptor ligands, especially for the treatment of obesity.
WO 00/12510 discloses pyrroloindoles, pyridoindoles and azepinoindoles as 5-HT2c receptor agonists, particluarly for the treatment of obesity.
WO 00/12482 discloses indazole derivatives as selective, directly active 5-HT2c receptor ligands, preferably 5-HT2c receptor agonists, particularly for use as anti-obesity agents.
WO 00/12502 discloses pyrroloquinolines as 5-HT2c receptor agonists, particularly for use as anti-obesity agents.
WO 00/35922 discloses 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)ones as 5HT2c agonists, which may be used for the treatment of obesity.
WO 00/44737 discloses aminoalkylbenzofurans as 5-HT2c agonists, which may be used for the treatment of obesity.
Further compounds reported to be 5HT2c receptor agonists are, for example, indazolylpropylamines of the type described in WO 00/12481; indazoles of the type described in WO 00/17170; piperazinylpyrazines of the type described in WO 00/76984; heterocycle fused xcex3-carbolines of the type described in WO 00/77001, WO 00/77002 and WO 00/77010; benzofurylpiperazines of the type described in WO 01/09111 and WO 01/09123; benzofurans of the type described in WO 01/09122; benzothiophenes of the type described in 01/09126; aminoalkylindazoles of the type described in WO 98/30548; indoles of the type described in WO 01/12603; indolines of the type described in WO 01/12602; pyrazino(aza)indoles of the type described in WO 00/44753 and tricyclic pyrroles or pyrazoles of the type described in WO 98/56768.
GB-B-1,457,005 discloses 1-piperazinyl-2-[2-(phenyl)ethenyl]-quinoxaline derivatives which exhibit anti-inflammatory activity.
Chem. Pharm. Bull. 1993, 41(10) 1832-1841 discloses 5-HT3 antagonists including 2-(4-methyl-1 -piperazinyl)-4-phenoxyquinoxaline.
GB-B-1,440,722 discloses 2-(1xe2x80x2-piperazinyl)-quinoxaline compounds having pharmaceutical activity against depression.
WO 96/11920 discloses CNS-active pyridinylurea derivatives.
WO 95/01976 discloses indoline derivatives active as 5-HT2c antagonists and of potential use in the treatment of CNS disorders.
WO 97/14689 discloses arylpiperazine cyclic amine derivatives, which are selective 5-HT1d receptor antagonists.
WO 98/42692 discloses piperazines derived from cyclic amines, which are selective antagonists of human 5-HT1a, 5-HT1d and 5-HT1b receptors.
GB-B-1,465,946 discloses substituted pyridazinyl, pyrimidinyl and pyridyl compounds which are active as xcex2-receptor blocking agents.
EP-A-711757 discloses [3-(4-phenyl-piperazin-1-yl)propylamino]-pyridine, pyrimidine and benzene derivatives as xcex1-adrenoceptor antagonists.
WO 99/03833 discloses arylpiperazine derivatives, which are 5-HT2 antagonists and 5-HT1a receptor agonists and therefore are useful as remedies or preventives for psychoneurosis.
WO 96/02525 discloses arylpiperazine-derived piperazide derivatives having 5-HT receptor antagonistic activity.
WO 99/58490 disloses aryl-hydronaphthalen-alkane amines which may effectuate partial or complete blockage of serotonergic 5-HT2c receptors in an organism.
It is an object of the present invention to provide new compounds.
Another object of the invention is a pharmaceutical composition comprising compounds for use in therapy as an active ingredient.
Finally, an object of the invention is a method of treatment or prophylaxis of a serotonin related disease, especially a disease related to the 5-HT2c receptor.
According to the invention novel compounds of the general formula (I) are provided: 
wherein
R1 is hydrogen, C1-C4-alkyl, C3-4-alkenyl, C1-4-acyl, C1-4-alkoxycarbonyl, 2-hydroxyethyl, 2-cyanoethyl, tetrahydropyran-2-yl, or a nitrogen protecting group;
R2 is hydrogen, C1-4-alkyl, hydoxymethyl, C1-4-alkoxymethyl, or fluoromethyl;
R3 and R4 independently of each other are hydrogen, halogen, methyl, C1-4-alkyl, aryl, heteroaryl wherein aryl and heteroaryl residues in turn may be substituted in one or more positions independently of each other by halogen, C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, C1-4-alkylsulphonyl, methanesulphonamido, acetyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, methylamino, dimethylamino, or acetamido; or
R3 and R4 together with the carbon atoms to which they are bound form a 5- or 6-membered aromatic or heteroaromatic ring, which optionally is independently substituted in one or more positions by halogen, methyl, methoxy, methylthio, methylsulphonyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethylthio, amino, methylamino, dimethylamino or acetamido;
R5 and R6 independently of each other are hydrogen, C1-C4-alkoxy-C2-C4-alkyl, hydroxy-C2-C4-alkyl, C1-C6-alkyl, C2-C6-acyl, aryl, heteroaryl, aryl-C1-C2-alkyl, heteroaryl-C1-C2-alkyl, aryl-C1-C2-acyl, heteroaryl-C1-C2-acyl, and wherein any aryl or heteroaryl, alone or as part of another group, may be independently substituted in one or more positions by C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, C2-4-acyl, C1-4-alkylsulphonyl, cyano, nitro, hydroxy, C2-3-alkenyl, C2-3-alkynyl, fluoromethyl, trifluoromethyl, trifluoromethoxy, halogen, dimethylamino, or methylamino; or
R5 and R6 together with the nitrogen atom to which they are bound form a saturated heterocyclic ring having 4-7 ring members which ring may contain an additional heteroatom and which may be substituted by methyl, oxo or hydroxy;
R7 is hydrogen or a substituent selected from halogen, methyl, methoxy, and ethoxy; and
n=1xe2x88x923;
and pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.
In case the compounds of formula (I) can be in the form of optical isomers, the invention comprises the racemic mixture as well as the individual enantiomers as such.
In case the compounds of formula (I) contain groups which may exist in tautomeric forms, the invention comprises the tautomeric forms of the compounds as well as mixtures thereof.
In case the compounds of formula (I) can be in the form of geometrical isomers, the invention comprises the geometrical isomers as well as mixtures thereof.
In another aspect, this invention provides a method for preparing a compound of this invention. The method includes converting a compound of formula (II): 
to the just-mentioned compound.
In formula (II), R3 and R4 independently of each other are hydrogen, halogen, methyl, C1-4-alkyl, aryl, heteroaryl wherein aryl and heteroaryl residues in turn may be substituted in one or more positions independently of each other by halogen, C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, C1-4-alkylsulphonyl, methanesulphonamido, acetyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, methylamino, dimethylamino or acetamido; or
R3 and R4 together with the carbon atoms to which they are bound form a 5- or 6-membered aromatic or heteroaromatic ring, which may be substituted in one or more positions by halogen, methyl, methoxy, methylthio, methylsulphonyl, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethylthio, amino, methylamino, dimethylamino or acetamido; and
each of Hal1 and Hal2, independently, is halogen.
In further another aspect, the invention provides the compounds according to formula (I) above for use in therapy.
Still another aspect of the invention provides a pharmaceutical composition comprising a compound according to formula (I) above as the active ingredient, preferably together with a pharmaceutically acceptable carrier and, if desired, other pharmacologically active agents.
In yet another aspect, the invention provides a method for the treatment of a human or animal subject suffering from a serotonin-related disease, particularly 5-HT2c receptor-related, especially eating disorders, particularly obesity; memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunctions, epilepsy and urinary disorders.
Another aspect of the invention provides the use of the compounds according to formula (I) above for the manufacture of a medicament for the treatment of a serotonin-related disease, particularly 5-HT2c receptor-related, especially eating disorders, particularly obesity; memory disorders; schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunctions, epilepsy and urinary disorders.
Finally a method for modulating 5HT2c receptor function is an aspect of the invention.
According to the present invention, a class of novel compounds has been developed which bind to the 5-HT2c receptor (agonists or antagonists) and which therefore may be used for the treatment of serotonin-related disorders.
First, the various terms used, separately and in combinations, in the above definition of the compounds having the general formula (I) will be explained.
By xe2x80x9cheteroatomxe2x80x9d is meant nitrogen, oxygen, sulphur, and in heteroaromatic rings, also selenium.
The term xe2x80x9carylxe2x80x9d includes phenyl, 1-naphthyl and 2-naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d includes five- and six-membered heteroaromatic rings such as pyrrole, imidazole, thiophene, furan, selenophene, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole and tetrazole.
C1-6-alkyl, which may be straight or branched, is preferably C1-4-alkyl. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.
C1-4-alkoxy may be straight or branched. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and tert-butoxy.
C2-4-alkenyl may be straight or branched. Exemplary alkenyl groups include vinyl, 2-propenyl and 1-methyl-2-propenyl.
C1-C4-alkoxy-C2-C4-alkyl may be straight or branched. Exemplary groups include 2-(methoxy)ethyl, 3-methoxy-1-propyl, 4-ethoxy-1-butyl and the like.
Exemplary aryl-C1-C2-acyl include benzoyl and phenylacetyl. Exemplary heteroaryl-C1-C2-acyl include nicotinoyl and 3-pyridinylacetyl and the like.
C2-4-acyl may be saturated or unsaturated. Exemplary acyl groups include acetyl, propionyl, butyryl, isobutyryl, and butenoyl (e.g. 3-butenoyl).
Halogen includes fluorine, chlorine and bromine.
Where it is stated above that aryl and heteroaryl residues may be substituted, this applies to aryl and heteroaryl per se as well as to any combined groups containing aryl or heteroaryl residues, such as heteroaryl-C1-C2-alkyl and aryl-C1-C2-acyl.
The term xe2x80x9cN-oxidesxe2x80x9d means that one or more nitrogen atoms, when present in a compound, are in N-oxide form (Nxe2x86x92O).
The term xe2x80x9cprodrug formsxe2x80x9d means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug. Reference is made to Goodman and Gilman""s, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, xe2x80x9cBiotransformation of Drugs, p. 13-15.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d mean salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, toluenesulphonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid, and the like.
R1 is preferably hydrogen or methyl. Most preferably R1 is hydrogen.
R1 may also serve as a nitrogen protecting group, and then R1 is t-butoxycarbonyl (t-BOC), benzyl, or trityl.
R2 is preferably hydrogen or methyl (especially in the 2-position of the piperazine ring).
R3 and R4 are preferably (independently) hydrogen, halogen or methyl. When R3 and R4 form a ring together with the ring carbons to which they are bound, such a ring is preferably benzene (to give quinoxaline) or thiophene (to give thieno[3,4-b]pyrazine). When substituted, the rings are preferably mono- or disubstituted, preferably by halogen or methyl.
When R7 is other than hydrogen it may occupy any available position of the phenyl ring.
The group xe2x80x94CH2N(R5)(R6) may be attached to the orto-, meta-, or the para position, relative to the alkylenedioxy side-chain, of the phenyl ring, preferably the meta position.
n in formula (I) is 1xe2x88x923 where n is the number of methylene groups n is preferably 1, having the meaning that the two oxygen atoms in formula (I) are spaced between a xe2x80x94CH2CH2xe2x80x94 group;
Preferred compounds of the general formula (I) above are:
2-(1-Piperazinyl)-3-{2-[3-(4-morpholinylmethyl)phenoxy]ethoxy}pyrazine;
2-(1-Piperazinyl)-3-{2-[3-(1-pyrrolidinylmethyl)phenoxy]ethoxy}pyrazine;
2-(1-Piperazinyl)-3-{2-[3-(4-methyl-1-piperazinylmethyl)phenoxy]ethoxy}pyrazine;
2-(1-Piperazinyl)-3-{2-[3-{(2-methoxyethyl)amino}methyl)phenoxy]ethoxy}pyrazine;
2-(1-Piperazinyl)-3-{2-[3-{(isopropylamino)methyl}phenoxy]ethoxy}pyrazine,
and their pharmacologically acceptable salts and solvates.
In another aspect, this invention relates to compounds of any of the formulae herein and their use as delineated herein, wherein R5 and R6 together with the nitrogen atom to which they are bound form a saturated heterocylic ring having 4-7 ring members, and which may contain an additional heteratom. Exemplary rings are azetidine, pyrrolidine, piperazine, homopiperazine, morpholine, thiomorpholine, or piperidine. The saturated heterocyclic ring may be substituted by methyl, oxo, or hydroxy.
As mentioned above, the compounds of the present invention are useful for the treatment (including prophylactic treatment) of serotonin-related disorders, especially 5-HT2c receptor-related, in a human being or in an animal (including e.g. pets), such as eating disorders, especially obesity; memory disorders, such as Alzheimer""s disease; schizophrenia; mood disorders, including, but not restricted to, major depression and bipolar depression, including both mild and manic bipolar disorder, seasonal affective disorder (SAD); anxiety disorders, including situational anxiety, generalised anxiety disorder, primary anxiety disorders (panic disorders, phobias, obsessive-compulsive disorders, and post-traumatic stress disorders), and secondary anxiety disorders (for example anxiety associated with substance abuse); pain; substance abuse; sexual dysfunctions; epilepsy and urinary disorders, such as urinary incontinence.
The compounds of the present invention in radiolabeled form, may be used as a diagnostic agent.
The compounds of the general formula (I) above may be prepared by a method of this invention, or by, in analogy with, a conventional method. This invention relates to methods of making compounds of any formulae herein comprising reacting any one or more of the compounds or formulae delineated herein including any processes delineated herein.
For example, as shown in Scheme 1, a compound of formula (I) may be prepared by first treating a compound of formula (II), wherein Hal is halogen and R3 and R4 are as defined above, with an appropriate piperazine of formula (III), wherein R1 and R2 have the same meaning as in formula (I) and where R1 may be a suitable nitrogen protecting group, such as trityl, benzyl or tert-butoxycarbonyl, to provide a compound of formula (IV). The reaction is carried out in a solvent, such as, acetonitrile, dioxane, tetrahydrofuran (THF), n-butanol, N,N-dimethylformamide (DMF), or in a mixture of solvents such as DMF/dioxane, optionally in the presence of a base, such as K2CO3, Na2CO3, Cs2CO3, NaOH, triethylamine, pyridine, or the like, at 0-200xc2x0 C. for 1-24 hours.
The compound of formula (IV) is reacted with a diol of formula (V), wherein n has the same meaning as in formula (I), to provide intermediate (VI). The reaction is carried out in a solvent, such as, dioxane, THF, DMF or pyridine, and the like, in the presence of a base such as K-t-BuO, Na-t-BuO, NaH, or the like, at 0-150xc2x0 C. for 1-24 hours.
Intermediate (VI) is reacted with a hydroxybenzaldehyde compound of formula (VII), wherein R7 has the same meaning as in formula (I), to provide the aldehyde intermediate (VIII). The reaction may be carried out in the presence of diethyl azodicarboxylate (DEAD) or 1,1xe2x80x2-azobis(N,N-dimethylfornamide) (cf. Tetrahedron Lett. 1995, 36, 3789-3792), preferably DEAD, and triphenylphosphine (PPh3) in a solvent such as THF or dichloromethane (Mitsunobu reaction; see: Org. React. 1992, 42, 335-656.).
Subjecting intermediate (VIII) to a standard reductive alkylation procedure (such as described in J. Org. Chem. 1996, 61, 3849-3862), with an appropriate amine of formula (IX), wherein R5 and R6 have the same meaning as in formula (I), results in a compound of this invention (I).
When R1 in formula (I) is a nitrogen protecting group as defined below, the subsequent N-deprotection may be performed under standard conditions, such as those described in Protective Groups in Organic Synthesis, John Wiley and Sons, 1991, to provide compounds of formula (I) wherein R1 is hydrogen. Nitrogen protecting groups are known in the art and include those described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991) and subsequent editions thereof. 
An obtained compound of formula (I) may be converted to another compound of formula (I) by methods well known in the art.
The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. A pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent, such as ether or in a mixture of ether and methanol, and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Examples of addition salt forming acids are maleic acid, fumaric acid, succinic acid, methanesulfonic acid, acetic acid, oxalic acid, benzoic acid, hydrochloric acid, sulphuric acid, phosphoric acid, and the like.
The compounds of formula (I) may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g., as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers. The separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.
In accordance with the present invention, the compounds of formula (I), in the form of free bases or salts with physiologically acceptable acids, can be brought into suitable galenic forms, such as compositions for oral use, for injection, for nasal spray administration or the like, in accordance with accepted pharmaceutical procedures. Such pharmaceutical compositions according to the invention comprise an effective amount of the compounds of formula (I) in association with compatible pharmaceutically acceptable carrier materials, or diluents, as are well known in the art. The carriers may be any inert material, organic or inorganic, suitable for enteral, percutaneous, subcutaneous or parenteral administration, such as: water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. Such compositions may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like.
The compositions according to the invention can e.g. be made up in solid or liquid form for oral administration, such as tablets, pills, capsules, powders, syrups, elixirs, dispersable granules, cachets, suppositories and the like, in the form of sterile solutions, suspensions or emulsions for parenteral administration, sprays, e.g. a nasal spray, transdermal preparations, e.g. patches, and the like.
As mentioned above, the compounds of the invention may be used for the treatment of serotonin-related disorders in a human being or an animal, such as eating disorders, particularly obesity, memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunctions, epilepsy and urinary disorders. The dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient""s age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy. The daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety.